ClinVar Genomic variation as it relates to human health
NM_025114.4(CEP290):c.2991+1655A>G
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_025114.4(CEP290):c.2991+1655A>G
Variation ID: 1337 Accession: VCV000001337.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q21.32 12: 88101183 (GRCh38) [ NCBI UCSC ] 12: 88494960 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_025114.4:c.2991+1655A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000012.12:g.88101183T>C NC_000012.11:g.88494960T>C NG_008417.2:g.46034A>G LRG_694:g.46034A>G LRG_694t1:c.2991+1655A>G - Protein change
- Other names
- 2991+1655A-G
- c.2991+1655A>G
- Canonical SPDI
- NC_000012.12:88101182:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- cryptic splice donor activation Variation Ontology [VariO:0374]
- PubMed: 16909394
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00029
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CEP290 | - | - |
GRCh38 GRCh37 |
3498 | 3662 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 8, 2021 | RCV000001400.13 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2023 | RCV000086286.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000558460.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 13, 2022 | RCV000763315.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2016 | RCV000678535.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 16, 2023 | RCV001196010.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000988884.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2020 | RCV001255341.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 25, 2019 | RCV001075828.4 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 23, 2017 | RCV001831503.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 12, 2023 | RCV001731267.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2023 | RCV003460403.1 | |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700700.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Aug 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001431671.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was … (more)
The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual. (less)
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Leber congenital amaurosis 10
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573634.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The CEP290 c.2991+1655A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The CEP290 c.2991+1655A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Sep 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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CEP290-related disorder
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983668.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: CEP290 c.2991+1655A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal … (more)
Variant summary: CEP290 c.2991+1655A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic intronic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and leads to insertion of a cryptic exon encoding a premature stop codon (den Hollander_2006). The variant allele was found at a frequency of 0.00013 in 31310 control chromosomes. c.2991+1655A>G has been reported in the literature in multiple individuals affected with CEP290-Related Disorders, namely Leber Congenital Amaurosis (example, den Hollander_2006). These data indicate that the variant is very likely to be associated with disease. Functional studies have reported ciliary and axonemal defects in patients with this variant (Gerard_2012). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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CEP290-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116303.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This variant (also referred to as IVS26+1655A>G) has been reported to create a strong splice-donor … (more)
The CEP290 c.2991+1655A>G variant is predicted to interfere with splicing. This variant (also referred to as IVS26+1655A>G) has been reported to create a strong splice-donor site and insert a cryptic exon in the CEP290 messenger RNA (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been reported, in the homozygous or compound heterozygous state along with a second CEP290 variant, in 16 of 76 unrelated patients with autosomal recessive Leber congenital amaurosis (den Hollander et al. 2006. PubMed ID: 16909394). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/1337/). Given the evidence, we interpret c.2991+1655A>G as pathogenic. (less)
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Pathogenic
(Dec 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017032.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial aplasia of the vermis
Meckel-Gruber syndrome Nephronophthisis
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000634646.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. … (more)
This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs281865192, gnomAD 0.02%). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 16909394, 17345604, 17964524). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS26+1655A>G and p.Cys998X. ClinVar contains an entry for this variant (Variation ID: 1337). Studies have shown that this variant results in insertion of 128bp of intronic sequence between exons 26 and 27 and introduces a premature termination codon (PMID: 16909394, 23344081). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome 5
Affected status: yes
Allele origin:
biparental
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Genomic Medicine Lab, University of California San Francisco
Accession: SCV004847136.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
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Pathogenic
(Aug 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246570.19
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 7
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138782.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jul 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001241465.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447854.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: male
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome 5
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366439.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM3,PP3,PP4.
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 10
Affected status: yes
Allele origin:
germline
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548124.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: WES
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Pathogenic
(Feb 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome 5
Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893992.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329242.8
First in ClinVar: Dec 06, 2016 Last updated: Apr 23, 2023 |
Comment:
Published functional studies demonstrate a damaging effect resulting in the insertion of an aberrant exon into approximately half of CEP290 transcripts and reduced CEP290 mRNA … (more)
Published functional studies demonstrate a damaging effect resulting in the insertion of an aberrant exon into approximately half of CEP290 transcripts and reduced CEP290 mRNA levels in comparison to wild type (Garanto et al., 2015; Gerard et al., 2012); This variant is associated with the following publications: (PMID: 22842229, 20683928, 20805370, 27106101, 31429209, 34196655, 23591405, 19823873, 24767827, 17564967, 17345604, 20130272, 23344081, 23343883, 18682808, 25761237, 20690115, 22355252, 28224992, 24223178, 29186038, 29178642, 30576320, 30193310, 31087526, 30559420, 31734136, 34327195, 32531858, 32865313, 29398085, 29518907, 33726816, 32037395, 31816670, 28619647, 28510626, 16909394) (less)
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bardet-Biedl syndrome 14
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004214830.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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pathologic
(Mar 29, 2012)
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no assertion criteria provided
Method: curation
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Joubert Syndrome and Related Disorders
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000058614.1
First in ClinVar: May 03, 2013 Last updated: May 03, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Jul 01, 2007)
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no assertion criteria provided
Method: literature only
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LEBER CONGENITAL AMAUROSIS 10
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021550.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 06, 2016 |
Comment on evidence:
In a consanguineous French Canadian family with 4 sibs affected by Leber congenital amaurosis-10 (LCA10; 611755), den Hollander et al. (2006) found that the affected … (more)
In a consanguineous French Canadian family with 4 sibs affected by Leber congenital amaurosis-10 (LCA10; 611755), den Hollander et al. (2006) found that the affected individuals had a splice defect in the CEP290 gene caused by an intronic mutation (2991+1655A-G) that created a strong splice donor site and inserted a cryptic exon in the CEP290 mRNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. Brancati et al. (2007) found that the 2991+1655A-G mutation, resulting in a C998X protein alteration, is associated with LCA only and is by far the most frequently observed mutation in the CEP290 gene, having been observed in 44 families. (less)
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804609.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 2
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922270.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932539.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037574.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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Pathogenic
(Sep 23, 2017)
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no assertion criteria provided
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002094277.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000118432.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_CEP290:c.2991%2B1655A>G
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not provided
(-)
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no classification provided
Method: literature only
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Leber congenital amaurosis 10
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000087012.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
Molecular and clinical analysis of 27 German patients with Leber congenital amaurosis. | Weisschuh N | PloS one | 2018 | PMID: 30576320 |
Joubert Syndrome. | Adam MP | - | 2017 | PMID: 20301500 |
Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2013 | PMID: 20301475 |
AON-mediated Exon Skipping Restores Ciliation in Fibroblasts Harboring the Common Leber Congenital Amaurosis CEP290 Mutation. | Gerard X | Molecular therapy. Nucleic acids | 2012 | PMID: 23344081 |
Antisense Oligonucleotide (AON)-based Therapy for Leber Congenital Amaurosis Caused by a Frequent Mutation in CEP290. | Collin RW | Molecular therapy. Nucleic acids | 2012 | PMID: 23343883 |
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. | Stone EM | American journal of ophthalmology | 2007 | PMID: 17964524 |
CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. | Brancati F | American journal of human genetics | 2007 | PMID: 17564967 |
Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. | Perrault I | Human mutation | 2007 | PMID: 17345604 |
Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. | den Hollander AI | American journal of human genetics | 2006 | PMID: 16909394 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CEP290 | - | - | - | - |
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Text-mined citations for rs281865192 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.